title: Glycine inhibitory dysfunction turns touch into pain through astrocyte-derived D-serine.
abstract: Glycine inhibitory dysfunction provides a useful experimental model for studying the mechanism of dynamic mechanical allodynia, a widespread and intractable symptom of neuropathic pain. In this model, allodynia expression relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astrocytes can regulate their activation through the release of the NMDAR coagonist d-serine. Recent studies also suggest that astrocytes potentially contribute to neuropathic pain. However, the involvement of astrocytes in dynamic mechanical allodynia remains unknown. Here, we show that after blockade of glycine inhibition, orofacial tactile stimuli activated medullary dorsal horn (MDH) astrocytes, but not microglia. Accordingly, the glia inhibitor fluorocitrate, but not the microglia inhibitor minocycline, prevented allodynia. Fluorocitrate also impeded activation of astrocytes and blocked activation of the superficial MDH neural circuit underlying allodynia, as revealed by study of Fos expression. MDH astrocytes are thus required for allodynia. They may also produce d-serine because astrocytic processes were selectively immunolabeled for serine racemase, the d-serine synthesizing enzyme. Accordingly, selective degradation of d-serine with d-amino acid oxidase applied in vivo prevented allodynia and activation of the underlying neural circuit. Conversely, allodynia blockade by fluorocitrate was reversed by exogenous d-serine. These results suggest the following scenario: removal of glycine inhibition makes tactile stimuli able to activate astrocytes; activated astrocytes may provide d-serine to enable NMDAR activation and thus allodynia. Such a contribution of astrocytes to pathological pain fuels the emerging concept that astrocytes are critical players in pain signaling. Glycine disinhibition makes tactile stimuli able to activate astrocytes, which may provide d-serine to enable NMDA receptor activation and thus allodynia.
authors.affiliation: Clermont Université, Université d'Auvergne, Neurobiologie de la douleur trigéminale, BP 10448, F-63000 Clermont-Ferrand, France Inserm, U929, F-63000 Clermont-Ferrand, CHU Clermont-Ferrand, Service d'Odontologie, F-63003 Clermont-Ferrand, France Inserm, U862, Neurocentre Magendie, F-33077 Bordeaux, France Université de Bordeaux, F-33077 Bordeaux, France.
authors.forename: Loïs S
authors.initials: LS
authors.lastname: Miraucourt
authors.forename: Cédric
authors.initials: C
authors.lastname: Peirs
authors.forename: Radhouane
authors.initials: R
authors.lastname: Dallel
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Voisin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002951:Citrates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005998:Glycine / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism*; D013126:Spinal Nerve Roots / Q000166:cytology; D013331:Strychnine / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D039481:CD11b Antigen; D002951:Citrates; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016761:Oncogene Proteins v-fos; C007744:fluorocitrate; D012694:Serine; D013331:Strychnine; D005998:Glycine